Overall survival for patients with multiple myeloma (MM) has been substantially extended by treatment with the proteosome inhibitor bortezomib and the immunomodulatory agent lenalidomide. However, these patients invariably relapse with resistant disease, emphasizing the need for new therapeutic targets for the treatment of refractory MM. Research supported by this SPORE grant has demonstrated that mucin 1 (MUCI) is aberrantly expressed in MM cells. MUCI consists of two subunits: an extracellular N-terminal mucin subunit and a transmembrane C-terminal oncogenic subunit (MUC1-C). MUC1-C interacts with galecfin-3 at the cell surface and is targeted to the nucleus and mitochondria. Of importance, MUC1-C promotes the growth and survival of MM cells. Studies supported by this grant have also demonstrated that MUC1-C is a druggable target. In this context, treatment of MM cell lines and primary cells from patients with MUC1-C peptide inhibitors is associated with the induction of late apoptosis/necrosis. Inhibition of MUC1-C is also effective in treating MM tumor xenografts in immunocompromised mice with prolonged regressions. Our studies have further shown that treatment of MM cells with MUC1-C inhibitors is associated with increases in reactive oxygen species (ROS), and marked down regulation of NADPH and glutathione (GSH). Moreover, this induction of oxidative stress by MUC1-C inhibitors is responsible for MM cell death, indicating that targeting MUC1-C has a unique mechanism of action. Our hypothesis is therefore that MUC1-C is a novel target for treatment of MM that is resistant to available therapies. The Specific Aims are: (1) To define the effects of inhibiting the MUC1-C intracellular domain in drug-resistant multiple myeloma cells; (2) To evaluate therapeutic approaches that target MUC1-C extracellular domains at the multiple myeloma cell surface; (3) To identify effective combination of MUC1-C inhibitors with other targeted agents for multiple myeloma treatment; and (4) To assess the pharmacodynamic effects of the MUC1-C inhibitor GO-203 in a Phase l/ll trial for patients with refractory multiple myeloma.